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Mackey J.R.,Cross Cancer Institute | Martin M.,Complutense University of Madrid | Pienkowski T.,European Health Center | Rolski J.,Podkarpackie Centrum Onkologii | And 26 more authors.
The Lancet Oncology | Year: 2013

Background: We compared standard adjuvant anthracycline chemotherapy with anthracycline-taxane combination chemotherapy in women with operable node-positive breast cancer. Here we report the final, 10-year follow-up analysis of disease-free survival, overall survival, and long-term safety. Methods: BCIRG 001 was an open label, phase 3, multicentre trial in which 1491 patients aged 18-70 years with node-positive, early breast cancer and a Karnofsky score of 80% or more were randomly assigned to adjuvant treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC) every 3 weeks for six cycles. Randomisation was stratified according to institution and number of involved axillary lymph nodes per patient (one to three vs four or more). Disease-free survival was the primary endpoint and was defined as the interval between randomisation and breast cancer relapse, second primary cancer, or death, whichever occurred first. Efficacy analyses were based on the intention-to-treat principle. BCIRG 001 is registered with ClinicalTrials.gov, number NCT00688740. Findings: Enrolement took place between June 11, 1997 and June 3, 1999; 745 patients were assigned to receive TAC and 746 patients were assigned to receive FAC. After a median follow-up of 124 months (IQR 90-126), disease-free survival was 62% (95% CI 58-65) for patients in the TAC group and 55% (51-59) for patients in the FAC group (hazard ratio [HR] 0·80, 95% CI 0·68-0·93; log-rank p=0·0043). 10-year overall survival was 76% (95% CI 72-79) for patients in the TAC group and 69% (65-72) for patients in the FAC group (HR 0·74, 0·61-0·90; log-rank p=0·0020). TAC improved disease-free survival relative to FAC irrespective of nodal, hormone receptor, and HER2 status, although not all differences were significant in these subgroup analyses. Grade 3-4 heart failure occurred in 26 (3%) patients in the TAC group and 17 (2%) patients in the FAC group, and caused death in two patients in the TAC group and four patients in the FAC group. A substantial decrease in left ventricular ejection fraction (defined as a relative decrease from baseline of 20% or more) was seen in 58 (17%) patients who received TAC and 41 (15%) patients who received FAC. Six patients who received TAC developed leukaemia or myelodysplasia, as did three patients who received FAC. Interpretation: Our results provide evidence that the initial therapeutic outcomes seen at the 5-year follow-up with a docetaxel-containing adjuvant regimen are maintained at 10 years. However, a substantial percentage of patients had a decrease in left ventricular ejection fraction, probably caused by anthracycline therapy, which warrants further investigation. Funding: Sanofi. © 2013 Elsevier Ltd.


Rolfo C.,University of Antwerp | Giovannetti E.,VU University Amsterdam | Hong D.S.,University of Houston | Bivona T.,University of California at San Francisco | And 14 more authors.
Cancer Treatment Reviews | Year: 2014

Introduction: Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) yields tumour responses in non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, even in long-lasting responses, resistance to EGFR TKIs invariably occurs. Areas covered: This review examines resistance mechanisms to EGFR TKI treatment, which mainly arise from secondary EGFR mutations. Other resistance-inducing processes include mesenchymal-epithelial transition factor (MET) amplification, epithelial-mesenchymal transformation, phenotypic change from NSCLC to small-cell lung carcinoma, and modifications in parallel signalling pathways. Current therapeutic strategies to overcome these EGFR TKI resistance mechanisms focus on the inhibition or blocking of multiple members of the ErbB family. Several molecules which target multiple ErbB receptors are being investigated in NSCLC and other indications including afatinib, an ErbB Family Blocker, as well as dacomitinib and lapatinib. Novel, non-quinazoline, EGFR inhibitors, that also target EGFR activating and resistance (T790M) mutations, are currently under clinical development. Other therapeutic strategies include inhibition of parallel and downstream pathways, using agents which target heat shock protein (HSP)90 or poly (ADP-ribose) polymerase in addition to mammalian target of rapamycin (mTOR), monoclonal antibodies against the insulin-like growth factor-1 receptor, and fulvestrant-mediated oestrogen receptor regulation. Conclusion: Improved understanding of mechanisms underlying resistance to EGFR TKIs emphasises the importance of a genotype-guided approach to therapy. Elucidation of resistance mechanisms is indeed crucial to target innovative therapeutic approaches and to improve the efficacy of anticancer regimes in NSCLC. © 2014 Elsevier Ltd.


PubMed | University of Washington, Comprehensive Cancer Centers Of Nevada And Us Oncology Research, Dana-Farber Cancer Institute, San Bernadino Urological Associates and 8 more.
Type: Journal Article | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen receptor (AR), and reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation. These open-label phase I and II studies [Androgen Receptor Modulation Optimized for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated the efficacy and safety of galeterone in patients with treatment-naive nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) and established a dose for further study.In ARMOR1, 49 patients received increasing doses (650-2,600 mg) of galeterone in capsule formulation; 28 patients in ARMOR2 part 1 received increasing doses (1,700-3,400 mg) of galeterone in tablet formulation for 12 weeks. Patients were evaluated biweekly for safety and efficacy, and pharmacokinetic parameters were assessed.In ARMOR1, across all doses, 49.0% (24/49) achieved a 30% decline in prostate-specific antigen (PSA; PSA30) and 22.4% (11/49) demonstrated a 50% PSA decline (PSA50). In ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30 was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was well tolerated; the most common adverse events were fatigue, increased liver enzymes, gastrointestinal events, and pruritus. Most were mild or moderate in severity and required no action and there were no apparent mineralocorticoid excess (AME) events.The efficacy and safety from ARMOR1 and ARMOR2 part 1 and the pharmacokinetic results support the galeterone tablet dose of 2,550 mg/d for further study. Galeterone was well tolerated and demonstrated pharmacodynamic changes consistent with its selective, multifunctional AR signaling inhibition.


Rolfo C.,University of Antwerp | Raez L.E.,Memorial Cancer Institute | Bronte G.,University of Palermo | Santos E.S.,Lynn Cancer Institute | And 4 more authors.
Expert Opinion on Investigational Drugs | Year: 2013

Introduction: Several new targeted agents with anti-angiogenic properties have been developed recently, including vandetanib, sunitinib, sorafenib, bevacizumab and others. Tumor development, progression, metastasis are strongly linked to angiogenesis. Targeted agents like bevacizumab, a monoclonal antibody which targets VEGF, have been fully developed in several solid tumors. These new agents strongly advocate that targeting angiogenesis is one of the best approaches for cancer therapy. Areas covered: Those agents that target additional pro-angiogenic intracellular signaling pathways beyond VEGF signaling have also the potential to contribute to anticancer therapies. The authors present here nintedanib (BIBF 1120), a triple angiokinase inhibitor. It targets not only VEGFRs, but also FGFR and PDGFR. All the available clinical information regarding Phase I-II trials and the toxicity and efficacy of BIBF 1120 both as single agent and in combination with cytotoxic agents in non-small cell lung cancer (NSCLC) is reviewed and discussed here. Expert opinion: Up till now, Phase I and II trials with nintedanib showed an improvement for survival of advanced NSCLC patients. Tolerability profile seems to be acceptable in these clinical trials. However, Phase III trials are mandatory to translate these findings into clinical practice. The research for predictive biomarkers could improve the success of these anti-angiogenic agents. © 2013 Informa UK, Ltd.


Ouhib Z.,Lynn Cancer Institute | Kasper M.,Lynn Cancer Institute | Perez Calatayud J.,Hospital La Fe | Perez Calatayud J.,Hospital Clinica Benidorm | And 4 more authors.
Brachytherapy | Year: 2015

Purpose: Nonmelanoma skin cancers (NMSCs) are the most common type of human malignancy. Although surgical techniques are the standard treatment, radiation therapy using photons, electrons, and brachytherapy (BT) (radionuclide-based and electronic) has been an important mode of treatment in specific clinical situations. The purpose of this work is to provide a clinical and dosimetric summary of the use of BT for the treatment of NMSC and to describe the different BT approaches used in treating cutaneous malignancies. Methods and Materials: A group of experts from the fields of radiation oncology, medical physics, and dermatology, who specialize in managing cutaneous malignancies reviewed the literature and compiled their clinical experience regarding the clinical and dosimetric aspects of skin BT. Results: A dosimetric and clinical review of both high dose rate (192Ir) and electronic BT treatment including surface, interstitial, and custom mold applicators is given. Patient evaluation tools such as staging, imaging, and patient selection criteria are discussed. Guidelines for clinical and dosimetric planning, appropriate margin delineation, and applicator selection are suggested. Dose prescription and dose fractionation schedules, as well as prescription depth are discussed. Commissioning and quality assurance requirements are also outlined. Conclusions: Given the limited published data for skin BT, this article is a summary of the limited literature and best practices currently in use for the treatment of NMSC. © 2015 American Brachytherapy Society.


Perez C.A.,University of Louisville | Velez M.,University of Miami | Raez L.E.,Memorial Cancer Institute | Raez L.E.,Florida International University | And 2 more authors.
Lung Cancer | Year: 2014

The large knowledge learned in molecular biology specifically in the oncology field during the last ten years has resulted in fruitful results for the treatment of non-small cell lung cancer. The first pathway to be effectively targeted in lung cancer was the epidermal growth factor receptor. The acceptance of epidermal growth factor receptor mutation as a strong predictive biomarker in non-small cell lung carcinoma has encouraged the search for more targets. In 2011, regulatory entities granted conditional approval to an anaplastic lymphoma kinase inhibitor (crizotinib) based on an impressive overall response rate in previously treated non-small cell lung cancer patients whose tumors harbored EML4/ALK translocations. The landmark approval of crizotinib based on early promising clinical data highlights the remarkable success of molecular medicine in lung cancer therapeutics. The cumulative data developed after that approval has confirmed the appropriateness of this decision as recently reported phase III has now demonstrated. Unfortunately, resistance to this agent invariably develops and we now face the challenge of understanding several resistance pathways and overcoming them with new and more potent compounds. New agents in clinical development such as alectinib, LDK378, AP26113, and AUY922 have not only demonstrated promising activity in crizotinib resistant patients, but also crossing new pharmacokinetic boundaries in ALK inhibition as potent CNS penetration. © 2014 Elsevier Ireland Ltd.


PubMed | Polytechnic University of Valencia, University of Valencia and Lynn Cancer Institute
Type: Journal Article | Journal: Journal of contemporary brachytherapy | Year: 2017

EsteyaA multidisciplinary team familiar with the treatment process was formed. This team developed a process map (PM) outlining the stages, through which a patient passed when subjected to the Esteya treatment. They identified potential failure modes (FM) and each individual FM was assessed for the severity (S), frequency of occurrence (O), and lack of detection (D). A list of existing quality management tools was developed and the FMs were consensually reevaluated. Finally, the FMs were ranked according to their risk priority number (RPN) and their S.146 FMs were identified, 106 of which had RPN 50 and 30 had S 7. After introducing the quality management tools, only 21 FMs had RPN 50. The importance of ensuring contact between the applicator and the surface of the patients skin was emphasized, so the setup was reviewed by a second individual before each treatment session with periodic quality control to ensure stability of the applicator pressure. Some of the essential quality management tools are already being implemented in the installation are the simple templates for reproducible positioning of skin applicators, that help marking the treatment area and positioning of X-ray tube.New quality management tools have been established as a result of the application of the failure modes and effects analysis (FMEA) treatment. However, periodic update of the FMEA process is necessary, since clinical experience has suggested occurring of further new possible potential failure modes.


Fox S.A.,Florida Atlantic University | Shanblatt A.A.,Florida Atlantic University | Beckman H.,Sinai Hospital of Detroit | Strasswimmer J.,Florida Atlantic University | And 2 more authors.
Lasers in Surgery and Medicine | Year: 2014

Background and Objectives: The number of cases of non-melanoma skin cancer (NMSC), which include squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), continues to rise as the aging population grows. Mohs micrographic surgery has become the treatment of choice in many cases but is not always necessary or feasible. Ablation with a high-poweredCO2 laser offers the advantage of highly precise, hemostatic tissue removal. However, confirmation of complete cancer removal following ablation is difficult. In this study we tested for the first time the feasibility of using Raman spectroscopy as an in situ diagnostic method to differentiate NMSC from normal tissue following partial ablation with a high-powered CO2 laser.Materials and Methods: Twenty-five tissue samples were obtained from eleven patients undergoing Mohs micrographic surgery to remove NMSC tumors. Laser treatment was performed with a SmartXide DOT Fractional CO2 Laser (DEKA Laser Technologies, Inc.) emitting a wavelength of 10.6 μm. Treatment levels ranged from 20mJ to 1200mJ total energy delivered per laser treatment spot (350μm spot size). Raman spectra were collected from both untreated and CO2 laser-treated samples using a 785nm diode laser. Principal Component Analysis (PCA) and Binary Logistic Regression (LR) were used to classify spectra as originating from either normal or NMSC tissue, and from treated or untreated tissue.Results: Partial laser ablation did not adversely affect the ability of Raman spectroscopy to differentiate normal from cancerous residual tissue, with the spectral classification model correctly identifying SCC tissue with 95% sensitivity and 100% specificity following partial laser ablation, compared with 92% sensitivity and 60% selectivity for untreated NMSC tissue. The main biochemical difference identified between normal and NMSC tissue was high levels of collagen in the normal tissue, which was lacking in the NMSC tissue.Conclusion: The feasibility of a combined high-powered CO2 laser ablation, Raman diagnostic procedure for the treatment of NMSC is demonstrated since CO2 laser treatment does not hinder the ability of Raman spectroscopy to differentiate normal from diseased tissue. This combined approach could be employed clinically to greatly enhance the speed and effectiveness ofNMSCtreatment in many cases. © 2014 Wiley Periodicals, Inc.


PubMed | Florida Atlantic University, Boca Raton and Lynn Cancer Institute
Type: Journal Article | Journal: Medical physics | Year: 2016

Exploring appropriate offset values in dose optimization with pencil beam (PB) algorithm to minimize dosimetric differences with plans calculated with Monte Carlo (MC) for lung cancer treatment with Stereotactic Body Radiotherapy (SBRT).20 cases of Non-Small Cell Lung Cancer, treated with gated full motion range SBRT were selected. According to the proximity of the Gross Tumor Volume (GTV) to the chest wall, two groups are defined: peripherally located when GTV merges with the chest wall for at least 50% of the lesion diameter, and centrally located when the GTV is surrounded by lung tissue. Treatment plans were created on 4D average intensity projection (AIP) CT set with Brainlab iPlanDose 4.1.2 planning system. The D97 of PTV was normalized to 50Gy using the fast PB and compared with MC. The optimized plan was then recomputed over each 4D respiratory phase, and compared with MC using the same plan MU s.The mean difference in the PB and MC D97 of the ITV was 10.5% (0.8%) of the prescription dose (50Gy). PB algorithm showed 2.3-2.4% less overestimation to the D97 of the ITV, when comparing to MC, in the maximum exhalation phase than in the maximal inhalation phase. Significantly smaller dose difference between PB and MC is also shown in plans for peripheral lesions (7.7 0.7%) versus for central lesions (12.70.8%) (p< 0.01).The dosimetric differences between PB and MC can be reasonably predicted depending on the location of lesion in the lung, and may be used as offset value in dose optimization with PB. Since the maximal exhalation phase demonstrates less dose discrepancy between the two algorithms than that in maximal inhalation phase, caution is suggested when the latter is included as a major phase portion in the respiration gated lung SBRT.


PubMed | Boca Raton Regional Hospital, Florida Atlantic University and Lynn Cancer Institute
Type: Journal Article | Journal: Medical physics | Year: 2017

To investigate the potential use of the Raven (LAP of America Laser Applications) for real time AQA of Cyberknife with InCise2 MLC (Accuray Medical).At setup, the Raven was rotated 45 on which an Accuray AQA cube was positioned. Three different AQA plans for fixed cone, InCise2MLC, and a modified MLC plan were delivered repeatedly ten times. The additional shapes in modified AQA plan enable additional reproducibility checks for all the MLC pairs. During the test, the cube was aligned by imbedded fiducials and irradiated. The two angled radiation beams aimed center tungsten ball of the cube and projected 45 to phosphor screen and registered by a CCD camera of the Raven device. The centricity of the metal ball in the irradiated field was then analyzed using Matlab codes.For AP images, the average offsets of X, Y, and radial directions are 0.24 0.04 mm, 0.25 0.02 mm and 0.35 0.03 mm respectively for the cone; 0.34 0.02 mm, 0.49 0.04 mm and 0.60 0.04 mm respectively for the MLC. For lateral images, they are 0.63 0.05 mm, 0.11 0.02 mm and 0.64 0.04 mm respectively for the cone, 0.79 0.08 mm, -0.23 0.06 mm and 0.82 0.09 mm respectively for the MLC. No inconsistent MLC shapes were found in the modified AQA group.The results are consistent with clinically acceptable values (1mm from baseline). The results suggest the potential of replacement of the standard AQA test with the novel real-time Raven device for Cyberknife daily QA. The modified MLC based AQA provides a more comprehensive MLC daily QA capability. Further improvements in its resolution and automatic analyzing capability are warranted.

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